PDBsum entry 2ph8

Hydrolase

PDB id

2ph8

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Contents

			Protein chain

					365 a.a. *

			Ligands

					SO4 ×2


					35A

			Waters ×293

* Residue conservation analysis

PDB id:

2ph8

Links
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Name:

Hydrolase

Title:

Crystal structure of human beta secretase complexed with inhibitor

Structure:

Beta-secretase 1. Chain: a. Fragment: protease domain (residues 43-446). Synonym: beta-site app cleaving enzyme 1, beta-site amyloid precursor protein cleaving enzyme 1, membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, asp 2, asp2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bace1, bace. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.70Å

R-factor:

0.186

R-free:

0.204

Authors:

S.Munshi

Key ref:

K.P.Moore et al. (2007). Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors. Bioorg Med Chem Lett, 17, 5831-5835. PubMed id: 17827011

Date:

10-Apr-07

Release date:

22-Apr-08

PROCHECK

	Headers

	References

Protein chain

P56817 (BACE1_HUMAN) - Beta-secretase 1 from Homo sapiens

Seq: Struc:					501 a.a. 365 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 2 residue positions (black crosses)



		Enzyme reactions

Enzyme class:

E.C.3.4.23.46 - memapsin 2.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

	Bioorg Med Chem Lett 17:5831-5835 (2007)
PubMed id: 17827011

Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors.
K.P.Moore, H.Zhu, H.A.Rajapakse, G.B.McGaughey, D.Colussi, E.A.Price, S.Sankaranarayanan, A.J.Simon, N.T.Pudvah, J.H.Hochman, T.Allison, S.K.Munshi, S.L.Graham, J.P.Vacca, P.G.Nantermet.

ABSTRACT

This letter describes replacements for the P3 amide moiety present in previously reported tertiary carbinamine macrolactones. Although P-gp efflux issues associated with these amide-macrolactones were solved and full brain penetration was measured in one case, potency was compromised in the process.

Literature references that cite this PDB file's key reference

PubMed id

Reference

19585951

P.Davies, and J.Koppel (2009).
Mechanism-based treatments for Alzheimer's disease.

Dialogues Clin Neurosci, 11, 159-169.

19085994

P.G.Nantermet, H.A.Rajapakse, M.G.Stanton, S.R.Stauffer, J.C.Barrow, A.R.Gregro, K.P.Moore, M.A.Steinbeiser, J.Swestock, H.G.Selnick, S.L.Graham, G.B.McGaughey, D.Colussi, M.T.Lai, S.Sankaranarayanan, A.J.Simon, S.Munshi, J.J.Cook, M.A.Holahan, M.S.Michener, and J.P.Vacca (2009).
Evolution of tertiary carbinamine BACE-1 inhibitors: Abeta reduction in rhesus CSF upon oral dosing.

ChemMedChem, 4, 37-40.

18446509

J.Rautio, K.Laine, M.Gynther, and J.Savolainen (2008).
Prodrug approaches for CNS delivery.

AAPS J, 10, 92.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.